Project summary: This project is designed to evaluate a new class of anti-cancer agents for treatment of invasive melanoma, pancreas, lung, and colon carcinomas. The study compounds are small, synthetic molecules that have not previously been used in people, and bind to a surface receptor, G protein- coupled estrogen receptor (GPER) on tumor cells that has not previously been targeted in cancer. Strong preliminary results indicate that the study compounds potentiate the efficacy of the new immune checkpoint inhibitors that are now the standard of care for metastatic melanoma. In this proposal, we will determine the biologically active enantiomer of the GPER agonist G-1, routes of administration that will have the most favorable pharmacokinetics and maximize the anti-cancer effects, assay clinical cancer samples for expression of GPER and downstream signaling molecules. Completion of the proposed work will contribute to the completion of IND-enabling work necessary to translate these discoveries to first in human trials.